Project Summary Aging is a universal and fundamental biological process from yeast to humans. It is known that larger animals live longer and that there is an association between the aging process and the metabolic rate. Even though aging is not defined as a condition to be treated by the US Federal Drug Administration, it is the most prevalent disease-related state that affects every human being, and the majority of human diseases can be classified as the diseases of aging. In this regard, there are few biomedical goals as important as the understanding of aging. Longevity is a consequence of complex processes with contributions from both genetic and environmental factors. Genomic, transcriptomic, and proteomic research tools have been applied to understand aging and age-related diseases. Recently, metabolite profiling has been employed to investigate the dynamics of metabolic flux and interaction between genetic and environmental factors. Metabolite profiling offers the quantitative analysis of numerous endogenous small molecules and their interactions in response to physiological and environmental changes. Our research interests are in understanding dynamics of metabolites during the aging process, especially accumulation of molecular damage. The proposed study will employ metabolite profiling to test the concepts of 'cellular damage accumulation' during aging, characterize their identity, and understand the underlying mechanisms. Although the concept of age-associated damage accumulation is not new, previous advances in this area have been limited by technology. What were needed are methods that go to sufficient depth in characterizing cellular components, whereby detecting numerous damage forms. Advances in sensitivity and specificity of this technology made it possible to analyze changes in more than 15,000 compounds from minimal amounts of tissues. Advanced technology, sensitivity of metabolite profiles and collaboration with Dr. Clary Clish, Director of Metabolite Profiling at the Broad Institute, will allow us to test questions which could not be addressed previously. Using this rapidly developing approach, we propose to advance the area of metabolomics of aging. We will be test the hypotheses that there are metabolites that change as a function of age, that they can be detected and analyzed by advanced metabolite profiling methods, and that they correlate with the development of age- related disease and treatments known to extend lifespan. To address these questions, we will characterize metabolites in rodent models characterized by differences in lifespan, identify candidate markers of aging, determine their basic properties, and characterize them in long-lived animal models.